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Testosterone
| CAS_supplemental = 57-85-2 (propionate ester) | ChemSpiderID = 5791 | ATC_prefix=G03 | ATC_suffix=BA03 | ATC_supplemental= | PubChem=6013 | DrugBank=DB00624 | C=19 | H=28 | O=2 | molecular_weight = 288.42 | bioavailability= low (due to extensive first pass metabolism) | metabolism = Liver, Testis and Prostate | elimination_half-life= 2-4 hours | excretion = Urine (90%), feces (6%) | pregnancy_category = X (USA), Teratogenic effects | legal_status = Schedule III (USA) Schedule IV (Canada) | routes_of_administration=Intramuscular injection, transdermal (cream, gel, or patch), sub-'Q' pellet | melting_point =155 | melting_high =156 | specific_rotation=+110,2° | sec_combustion=−11080 kJ/mol }} '''Testosterone' is a steroid hormone from the androgen group and is found in mammals, reptiles, birds, and other vertebrates. In mammals, testosterone is primarily secreted in the testes of males and the ovaries of females, although small amounts are also secreted by the adrenal glands. It is the principal male sex hormone and an anabolic steroid. In men, testosterone plays a key role in the development of male reproductive tissues such as the testis and prostate as well as promoting secondary sexual characteristics such as increased muscle, bone mass and hair growth. In addition, testosterone is essential for health and well-being as well as the prevention of osteoporosis. On average, an adult human male body produces about ten times more testosterone than an adult human female body, but females are, from a behavioral perspective (rather than from an anatomical or biological perspective ), more sensitive to the hormone. However, the overall ranges for male and female are very wide, such that the ranges actually overlap at the low end and high end respectively . Testosterone is conserved through most vertebrates, although fish make a slightly different form called 11-ketotestosterone. Its counterpart in insects is ecdysone. These ubiquitous steroids suggest that sex hormones have an ancient evolutionary history. Of interest to psychologists are: The link between testosterone and thoughts, feelings and behavior Testosterone has been associated with a broad array of psychological effects. Testosterone and human relationships * Studies show that falling in love decreases men's testosterone levels while increasing women's testosterone levels. It is speculated that these changes in testosterone result in the temporary reduction of differences in behavior between the sexes.Marazziti D, Canale D. 2004.Hormonal changes when falling in love. Psychoneuroendocrinology 29(7): 931-936. Testosterone and risk taking * Recent studies suggest that testosterone level plays a major role in risk-taking during financial decisions. *Fatherhood also decreases testosterone levels in men, suggesting that the resulting emotional and behavioral changes promote paternal care.Berg SJ, Wynne-Edwards KE. 2001. Changes in testosterone, cortisol, and estradiol levels in men becoming fathers. Mayo Clinic Proceedings 76(1): 582-592. Testosterone and aggression There is strong evidence in animals that testosterone is directly associated with aggression, although this correlation is not as strong in humans.Simpson, K (2001) The role of testosterone in aggression. MJM, 6, 32-40 Full text In human studies a relationship has been found between measures of testosterone in adolescent males and aggression Olweus D, Mattson A, Schalling D, Low H. (1988) Circulating testosterone levels and aggression in adolescent males: a causal analysis. Psychosomatic Medicine 50: 261-272. with similar results found in women Ehlers CL, Rickler KC, Hovey JE. (1980) A possible relationship between plasma testosterone and aggressive behavior and socialdominance in man. Psychosomatic Medicine 36: 469-475. Testosterone and sexuality Testosterone and social dominance Testosterone and mental disorders Depression - Testosterone Physiological effects In general, androgens promote protein synthesis and growth of those tissues with androgen receptors. Testosterone effects can be classified as virilizing and anabolic, although the distinction is somewhat artificial, as many of the effects can be considered both. Testosterone is anabolic, meaning it builds up bone and muscle mass. * Anabolic effects include growth of muscle mass and strength, increased bone density and strength, and stimulation of linear growth and bone maturation. * Androgenic effects include maturation of the sex organs, particularly the penis and the formation of the scrotum in the fetus, and after birth (usually at puberty) a deepening of the voice, growth of the beard and axillary hair. Many of these fall into the category of male secondary sex characteristics. Testosterone effects can also be classified by the age of usual occurrence. For postnatal effects in both males and females, these are mostly dependent on the levels and duration of circulating free testosterone. Prenatal Most of the prenatal androgen effects occur between 7 and 12 weeks of the gestation. *Genital virilization (midline fusion, phallic urethra, scrotal thinning and rugation, phallic enlargement); although the role of testosterone is far smaller than that of Dihydrotestosterone. *Development of prostate and seminal vesicles *Gender identity Early infancy Early infancy androgen effects are the least understood. In the first weeks of life for male infants, testosterone levels rise. The levels remain in a pubertal range for a few months, but usually reach the barely detectable levels of childhood by 4–6 months of age. The function of this rise in humans is unknown. It has been speculated that "brain masculinization" is occurring since no significant changes have been identified in other parts of the body. Surprisingly, the male brain is masculinized by testosterone being aromatized into estrogen, which crosses the blood-brain barrier and enters the male brain, whereas female fetuses have alpha-fetoprotein which binds up the estrogen so that female brains are not affected.http://homepage.psy.utexas.edu/homepage/class/psy308/Humm/ReviewofSexualDifferentiation Pre-peripubertal Pre- Peripubertal effects are the first observable effects of rising androgen levels at the end of childhood, occurring in both boys and girls. *Adult-type body odour *Increased oiliness of skin and hair, acne *Pubarche (appearance of pubic hair) *Axillary hair *Growth spurt, accelerated bone maturation *Hair on upper lip and sideburns. Pubertal Pubertal effects begin to occur when androgen has been higher than normal adult female levels for months or years. In males, these are usual late pubertal effects, and occur in women after prolonged periods of heightened levels of free testosterone in the blood. *Enlargement of sebaceous glands. This might cause acne. *Phallic enlargement or clitoromegaly *Increased libido and frequency of erection or clitoral engorgement *Production of adult patterns of hair growth eg Pubic hair extends to thighs and up toward navel andAxillary hair appears. *Subcutaneous fat in face decreases *Increased muscle strength and mass *Deepening of voice *Growth of the Adam's apple *Growth of spermatogenic tissue in testicles, male fertility *Growth of jaw, brow, chin, nose, and remodeling of facial bone contours *Shoulders become broader and rib cage expands *Completion of bone maturation and termination of growth. This occurs indirectly via estradiol metabolites and hence more gradually in men than women. Adult Adult testosterone effects are more clearly demonstrable in males than in females, but are likely important to both sexes. Some of these effects may decline as testosterone levels decrease in the later decades of adult life. *Libido and clitoral engorgement/penile erection frequency *Regulates acute HPA (Hypothalamic–pituitary–adrenal axis) response under dominance challenge *Mental and physical energy *Maintenance of muscle trophism * In animals (grouse and sand lizards), higher testosterone levels have been linked to a reduced immune system activity. Testosterone seems to have become part of the honest signaling system between potential mates in the course of evolution. *The most recent and reliable studies have shown that testosterone does not cause or produce deleterious effects on prostate cancer. In people who have undergone testosterone deprivation therapy, testosterone increases beyond the castrate level have been shown to increase the rate of spread of an existing prostate cancer. * Recent studies have shown conflicting results concerning the importance of testosterone in maintaining cardiovascular health. Nevertheless, maintaining normal testosterone levels in elderly men has been shown to improve many parameters which are thought to reduce cardiovascular disease risk, such as increased lean body mass, decreased visceral fat mass, decreased total cholesterol, and glycemic control. *Under dominance challenge, may play a role in the regulation of the fight-or-flight response *Testosterone regulates the population of thromboxane A2 receptors on megakaryocytes and platelets and hence platelet aggregation in humans , showing adult male testosterone levels in light blue at center-left.]] * Testosterone is necessary for normal sperm development. It activates genes in Sertoli cells, which promote differentiation of spermatogonia. Brain As testosterone affects the entire body (often by enlarging; men have bigger hearts, lungs, liver, etc.), the brain is also affected by this "sexual" differentiation; the enzyme aromatase converts testosterone into estradiol that is responsible for masculinization of the brain in male mice. In humans, masculinization of the fetal brain appears, by observation of gender preference in patients with congenital diseases of androgen formation or androgen receptor function, to be associated with functional androgen receptors. There are some differences between a male and female brain (possibly the result of different testosterone levels), one of them being size: the male human brain is, on average, larger. In a Danish study from 2003, men were found to have a total myelinated fiber length of 176,000 km at the age of 20, whereas in women the total length was 149,000 km.Marner L, Nyengaard JR, Tang Y, Pakkenberg B. (2003). Marked loss of myelinated nerve fibers in the human brain with age. J Comp Neurol. 462(2):144-52. However, women have more dendritic connections between brain cells. A study conducted in 1996 found no immediate short term effects on mood or behavior from the administration of supraphysiologic doses of testosterone for 10 weeks on 43 healthy men. Another study found a correlation between testosterone and risk tolerance in career choice among women.Testosterone Affects Some Women's Career Choices Literature suggests that attention, memory, and spatial ability are key cognitive functions affected by testosterone in humans. Preliminary evidence suggests that low testosterone levels may be a risk factor for cognitive decline and possibly for dementia of the Alzheimer’s type, a key argument in life extension medicine for the use of testosterone in anti-aging therapies. Much of the literature, however, suggests a curvilinear or even quadratic relationship between spatial performance and circulating testosterone, where both hypo- and hypersecretion (over- and under-sectretion) of circulating androgens have negative effects on cognition and cognitively modulated aggressivity, as detailed above. Contrary to what has been postulated in outdated studies and by certain sections of the media, aggressive behaviour is not typically seen in hypogonadal men who have their testosterone replaced adequately to the eugonadal/normal range. In fact, aggressive behaviour has been associated with hypogonadism and low testosterone levels and it would seem as though supraphysiological and low levels of testosterone and hypogonadism cause mood disorders and aggressive behaviour, with eugondal/normal testosterone levels being important for mental well-being. Testosterone depletion is a normal consequence of aging in men. One possible consequence of this could be an increased risk for the development of Alzheimer’s disease. Biochemistry Biosynthesis , showing testosterone near bottom.]] Like other steroid hormones, testosterone is derived from cholesterol (see figure to the right). The first step in the biosynthesis involves the oxidative cleavage of the sidechain of cholesterol by CYP11A, a mitochondrial cytochrome P450 oxidase with the loss of six carbon atoms to give pregnenolone. In the next step, two additional carbon atoms are removed by the CYP17A enzyme in the endoplasmic reticulum to yield a variety of C19 steroids. In addition, the 3-hydroxyl group is oxidized by 3-β-HSD to produce androstenedione. In the final and rate limiting step, the C-17 keto group androstenedione is reduced by 17-β hydroxysteroid dehydrogenase to yield testosterone. The largest amounts of testosterone (>95%) are produced by the testes in men. It is also synthesized in far smaller quantities in women by the thecal cells of the ovaries, by the placenta, as well as by the zona reticularis of the adrenal cortex in both sexes. In the testes, testosterone is produced by the Leydig cells. The malegenerative glands also contain Sertoli cells which require testosterone for spermatogenesis. Like most hormones, testosterone is supplied to target tissues in the blood where much of it is transported bound to a specific plasma protein, sex hormone binding globulin (SHBG). Regulation In males, testosterone is primarily synthesized in Leydig cells. The number of Leydig cells in turn is regulated by luteinizing hormone (LH) and follicle stimulating hormone (FSH). In addition, the amount of testosterone produced by existing Leydig cells is under the control of LH which regulates the expression of 17-β hydroxysteroid dehydrogenase. The amount of testosterone is synthesized is regulated by the hypothalamic-pituitary-testicular axis (see figure to the right). When testosterone levels are low, gonadotropin-releasing hormone (GnRH) is released by the hypothalamus which in turn stimulates the pituitary gland to release FSH and LH. These later two hormones stimulate the testis to synthesize testosterone. Finally increasing levels of testosterone through a in a negative feedback loop act on the hypothalamus and pituitary to inhibit the release of GnRH and FSH/LH respectively. Environmental factors affecting testosterone levels include: * Loss of status or dominance in men may result in a decreased testosterone level. * Implicit power motivation predicts an increased testosterone release in men. * Aging reduces testosterone release. * Hypogonadism * Sleep (REM dream) increases nocturnal testosterone levels. * Resistance training increases testosterone levels, however, in older men, that increase can be avoided by protein ingestion. * Zinc deficiency lowers testosterone levels but over supplementation has no effect on serum testosterone. *Licorice. The active ingredient in licorice root, glycyrrhizinic acid has been linked to small, clinically non-significant decreases in testosterone levels. In contrast, a more recent study found that licorice administration produced a substantial testosterone decrease in a small, female-only sample. Metabolism Approximately 7% of testosterone is reduced to 5α-dihydrotestosterone (DHT) by the cytochrome P450 enzyme 5α-reductase, an enzyme highly expressed in male accessory sex organs and hair follicles. Approximately 0.3% of testosterone is converted into estradiol by aromatase (CYP19A1) an enzyme expressed in the brain, liver, and adipose tissues. DHT is a more potent form of testosterone while estradiol has completely different activities (feminization) compared to testosterone (masculinization). Finally testosterone and DHT may be deactivated or cleared by enzymes that hydroxylate at the 6, 7, 15 or 16 positions. Mechanism of action The effects of testosterone in humans and other vertebrates occur by way of two main mechanisms: by activation of the androgen receptor (directly or as DHT), and by conversion to estradiol and activation of certain estrogen receptors. Free testosterone (T) is transported into the cytoplasm of target tissue cells, where it can bind to the androgen receptor, or can be reduced to 5α-dihydrotestosterone (DHT) by the cytoplasmic enzyme 5-alpha reductase. DHT binds to the same androgen receptor even more strongly than T, so that its androgenic potency is about 5 times that of T. The T-receptor or DHT-receptor complex undergoes a structural change that allows it to move into the cell nucleus and bind directly to specific nucleotide sequences of the chromosomal DNA. The areas of binding are called hormone response elements (HREs), and influence transcriptional activity of certain genes, producing the androgen effects. It is important to note that if there is a 5-alpha reductase deficiency, the body (of a human) will continue growing into a female with testicles. Androgen receptors occur in many different vertebrate body system tissues, and both males and females respond similarly to similar levels. Greatly differing amounts of testosterone prenatally, at puberty, and throughout life account for a share of biological differences between males and females. The bones and the brain are two important tissues in humans where the primary effect of testosterone is by way of aromatization to estradiol. In the bones, estradiol accelerates maturation of cartilage into bone, leading to closure of the epiphyses and conclusion of growth. In the central nervous system, testosterone is aromatized to estradiol. Estradiol rather than testosterone serves as the most important feedback signal to the hypothalamus (especially affecting LH secretion). In many mammals, prenatal or perinatal "masculinization" of the sexually dimorphic areas of the brain by estradiol derived from testosterone programs later male sexual behavior. The human hormone testosterone is produced in greater amounts by males, and less by females. The human hormone estrogen is produced in greater amounts by females, and less by males. Testosterone causes the appearance of masculine traits (i.e., deepening voice, pubic and facial hairs, muscular build, etc.) Like men, women rely on testosterone to maintain libido, bone density and muscle mass throughout their lives. In men, inappropriately high levels of estrogens lower testosterone, decrease muscle mass, stunt growth in teenagers, introduce gynecomastia, increase feminine characteristics, and decrease susceptibility to prostate cancer, reduces libido and causes erectile dysfunction and can cause excessive sweating and hot flushes. However, an appropriate amount of estrogens is required in the male in order to ensure well-being, bone density, libido, erectile function, etc. Therapeutic use Testosterone therapy is a form of hormone therapy in which testosterone is administered to supplement existing low level of the hormone. See also *Fetal testosterone theory of autism *Male *Testosterone poisoning *Testosterone spray Notes References *Ajayi AAL, Mathur R, Halushka PV. Testosterone increases platelet TXA2 receptor density and aggregation responses (1995). Circulation 91 : 2742-7. *Ajayi AAL, Halushka PV. Castration reduces platelet TXA2 receptor density and aggregability (2005). QJM 98 : 349-57. * * * * (Seventh edition by J.D. Wilson and R.H. Williams, 1985, ISBN 072161082X.) * * * * * * * External links * NIST entry for Testosterone * NIST results of search for Testosterone (Shows androstenone.) * Results of research on the efficacy of differing body locations for the absorption of topical testosterone creams * A general pdf booklet that discusses the history, uses in Men, various treatments available, etc. * "Calls for testosterone trials in CHD " Category:Androgens Category:Erectile dysfunction drugs Category:Neuroendocrinology Category:Anabolic steroids